Although major progress in clinical transplantation has been achieved during the past decade, many potential recipients waiting for solid organ transplant face death due to the grim reality of a severe shortage of donor organs for transplantation. This serious shortage of organs has engendered heightened interest in the field of cross species transplantation. Organs from swine are viewed as the most promising candidates for transplants int humans. The major barrier for successful hyperacute rejection and approaches to abrogate it have made it likely that in the very near future, hyperacute rejection might be overcome. It will then be necessary to define other mechanisms of xenograft rejection mediated by cellular and humoral pathways of immune system. The overall goal of the application is to define the immune mechanisms mediating cellular rejection of porcine xenografts. To accomplish these goals the applicant will carry out the following experiments. 1) Characterize the in vivo response to porcine cell transplant using human peripheral blood leukocyte reconstituted severe combined immune deficient mice (Hu-PBL- SCID) and test the hypothesis that xenograft infiltrating cells will consist of both CD8+ and CD4+ T cells. Further, CD4+ T cells may recognize porcine xenoantigens by both direct and indirect pathways depending upon the SLA class II expression of transplanted cells and the presence or absence of passenger leukocytes. 2) Characterize the indirect human T cell anti-porcine xeno-response and test the hypothesis that CD4+ cells primarily recognize peptides derived from SLA class I or II molecules presented by autologous antigen presenting cells and 3) Determine the role of CD4+ and CD8+ T cells specific for porcine xenoantigens in xenograft rejection. Using the Hu-PBL-SCID model and in vivo transfer experiments they will identify the role of both CD4+ and CD8+ T cells, individually and in combination, at inducing xenograft rejection. The cytokines involved in the rejection process and the role of CD4+ T cells recognizing porcine xenoantigens either by direct or indirect pathways will also be determined. Their long term goals are to develop new immunological approaches to prevent, through tolerance induction, or to treat human anti-porcine xenograft rejection based on knowledge of the immunological mechanisms of human anti-porcine cellular responses acquired through the studies proposed in their application.